RESUMO
While myelodysplastic syndromes with del(5q) (del(5q) MDS) comprises a well-defined hematological subgroup, the molecular basis underlying its origin remains unknown. Using single cell RNA-seq (scRNA-seq) on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Interestingly, both del(5q) and non-del(5q) cells present similar transcriptional lesions, indicating that all cells, and not only those harboring the deletion, may contribute to aberrant hematopoietic differentiation. However, gene regulatory network (GRN) analyses reveal a group of regulons showing aberrant activity that could trigger altered hematopoiesis exclusively in del(5q) cells, pointing to a more prominent role of these cells in disease phenotype. In del(5q) MDS patients achieving hematological response upon lenalidomide treatment, the drug reverts several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remain, which may be responsible for potential future relapses. Moreover, lack of hematological response is associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study reveals transcriptional alterations that could contribute to the pathogenesis and treatment response of del(5q) MDS.
Assuntos
Antígenos CD34 , Deleção Cromossômica , Cromossomos Humanos Par 5 , Células-Tronco Hematopoéticas , Lenalidomida , Síndromes Mielodisplásicas , Análise de Célula Única , Humanos , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Antígenos CD34/metabolismo , Cromossomos Humanos Par 5/genética , Masculino , Feminino , Idoso , Redes Reguladoras de Genes/efeitos dos fármacos , Pessoa de Meia-Idade , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Transcriptoma , Idoso de 80 Anos ou mais , RNA-Seq , Perfilação da Expressão GênicaRESUMO
Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For "fit patients" in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the "standard of care" for selected patients. On the other hand, for "unfit patients", azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease.